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WO1989009767A1 - Composes de carbamoyle-2-pyrrolidinone - Google Patents

Composes de carbamoyle-2-pyrrolidinone Download PDF

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Publication number
WO1989009767A1
WO1989009767A1 PCT/JP1989/000401 JP8900401W WO8909767A1 WO 1989009767 A1 WO1989009767 A1 WO 1989009767A1 JP 8900401 W JP8900401 W JP 8900401W WO 8909767 A1 WO8909767 A1 WO 8909767A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
hydrogen atom
lower alkyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1989/000401
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English (en)
Japanese (ja)
Inventor
Makoto Kajitani
Etsuo Hasegawa
Akihiro Kawaguchi
Junji Yamamoto
Katsuo Toide
Takaji Honna
Mitsugi Yasumoto
Nobuo Kasahara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taiho Pharmaceutical Co Ltd
Original Assignee
Taiho Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP63093968A external-priority patent/JP2611803B2/ja
Priority claimed from JP63093967A external-priority patent/JP2611802B2/ja
Application filed by Taiho Pharmaceutical Co Ltd filed Critical Taiho Pharmaceutical Co Ltd
Priority to KR1019890702310A priority Critical patent/KR910009934B1/ko
Priority to EP89904600A priority patent/EP0373226B1/fr
Priority to DE68916198T priority patent/DE68916198T2/de
Publication of WO1989009767A1 publication Critical patent/WO1989009767A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel carno- * moyl-2—pyrrolidinone compound, a brain function-improving agent containing the compound, and a brain metabolism-activating agent containing the compound. .
  • L-Birmoyl 2 -pyrrolidinone compound is a herbicide in France Patent No. 2018820, and is described in Agriculture and Horticulture in Japanese Patent Publication No. 52-25026.
  • a fungicide for France Patent No. 2018820 is described in Agriculture and Horticulture in Japanese Patent Publication No. 52-25026.
  • No. 6265, 55-81857, and 55-153763 which are described as a citrus fruit refining agent, they are used as a brain function improving agent and a brain metabolism activating / protecting agent as in the present invention. There is no description.
  • senile dementia is expected to increase in the number of patients as it ages in recent years, and it is becoming a serious medical and social problem.
  • various anti-dementia drugs have been researched and developed, but compounds with sufficient efficacy so far have not been found. Nevertheless, the emergence of such therapeutic drugs has been desired.
  • the purpose of the present invention is to provide a therapeutic agent for such senile dementia, It is an object of the present invention to provide a novel lipamoyl-2-pyrrolidinone compound which is extremely useful as a cerebral function improving agent and a brain metabolic activation protecting agent.
  • the present invention has the general formula
  • R 1 represents a hydrogen atom, a hydroxyl group, or a lower alkyl group which may be substituted with a hydroxyl group
  • R 2 represents a methoxy group or a lower alkyl group as a substituent. It indicates a phenyl group, a tetrahedral naphthyl group, a pyridyl group or a thiazolyl group which may have a mino group.
  • R 1 is a hydrogen atom, an unsubstituted lower alkyl group, and R 2 is not an unsubstituted phenyl group.
  • Vamoyl 2 related to pyrrolidinone compounds.
  • the lower alkyl group which may be substituted by the hydroxyl group represented by R 1 is methyl, ethyl, or II.
  • straight-chain or sheet-like alkyl groups of 5 to 5 and as the lower alkyl group substituted by a hydroxyl group, a hydroxyalkyl group of 1 to 5 may be used.
  • alkylamino group represented by R 2 a straight-chain or branched alkyl group having 1 to 3 carbon atoms is substituted.
  • Alkyl amino groups that have been ring-closed such as methylamino, methylamino, methylamino, ethylamino, etc. Examples include mino, propinorea mino, jib mouth pinoreaminopiperidino, piperazino group, and the like.
  • R 2 in the above general formula (1) is a phenyl group having a substituent
  • the number of the substituents is preferably from] to 3 times. No.
  • R ' is a hydrogen atom, a hydroxyl group, a methyl group, a hydroxymethyl group
  • R 2 is Phenyl, tetrahydronaphthyl, and pyridyl groups each having 1 to 3 methoxy groups or a dimethylamino group
  • the additional r Ah Ru of compounds with Chi a zone Li Le group is not to good or
  • Ri Oh R 1 is hydrogen atom, with water acid radical, R: to have a force '' menu preparative key sheet group
  • More preferred are compounds of the general formula (1), which are a phenyl group or a tetrahydronaphthyl group.
  • R 1 is a hydrogen atom, a hydroxyl group, or a lower alkyl group which may be substituted with a hydroxyl group
  • R 3 is a substitution group.
  • Lubamoyl-2—pyrrolidinone compound has excellent function-improving activity, brain metabolic activation / protection, and senile anti-dementia activity. Was found.
  • the present invention provides a cerebral activity improving agent and a metabolic activation ⁇ protective agent containing an effective amount of the compound of the above general formula (2) and a pharmacologically acceptable carrier. It is something.
  • the present invention provides a method for improving brain function and promoting brain metabolism, which comprises administering to a patient an effective amount of the compound of the above general formula (2). It is.
  • the lower alkoxy group represented by R 3 is a straight-chain or branched alkoxy group having 1 to 5 carbon atoms.
  • the halogen atom is fluorine.
  • Chlorine, bromine, iodine, etc., as the halogenomethyl group there may be mentioned, for example, tri-nor- olemethyl, chloromethyl, etc. .
  • R 3 in the above general formula (2) is a phenyl group having a substituent
  • the number of the substituent is preferably 1 to 3.
  • the compound of the above general formula ( ⁇ has the following drug S action. (1) Improves brain damage under hypoxic condition (anoxia) You
  • the compounds of the present invention are useful as medicines, especially as a result of intellectual or nervous breakdown, loss of memory, senile or intellectual fatigue, cerebrovascular dementia, cerebral disorders.
  • a Le Tsu high- M a type Addicted ⁇ of therapy place either Ri is rather than that you to use doctors Ru this and the force f in, and other brain function improving drugs or brain metabolism vehicle active ⁇ protection drugs of its It is useful.
  • the compounds of the present invention can be synthesized by any of the following methods. Wear .
  • the reaction between the compound (3) and the compound (4) is usually carried out in a solvent.
  • the solvent is not particularly limited as long as it does not participate in the reaction and is generally an ethyl ether, a dioxane, or a tetrahedral port.
  • Halogenated hydrocarbons such as methylene chloride, methylene chloride, black mouth holme, dichloroethane, tetrachloride carbon, benzene, etc.
  • Aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethylsulfoxide, hexametinolenic acid tris
  • Non-porous polar solvents such as amides are used.
  • the ratio of the compound (3) to the compound (4) may be appropriately selected, but the compound (4) is generally used in an amount of 1 to 2 times the amount of the compound (3). It is advantageous to use an equimolar amount.
  • the reaction temperature may be appropriately selected, but is generally from room temperature to 150, preferably at about the reflux temperature of the solvent, and the reaction proceeds more efficiently.
  • the compound (5) obtained in this way is isolated or, if not isolated, is reacted with an amide (6). I can do it.
  • the reaction is usually carried out in a solvent, and as long as the solvent does not participate in the reaction, there is no particular limitation.
  • the compound (3) and the compound The solvent in the (fe) of the product (4) is used.
  • the compound (5) and the amide (6) are used in an amount of 1 to 2 times, preferably, an equimolar amount of the amide (6) to the compound (5).
  • the reaction temperature may be appropriately selected, but is generally from room temperature to 150, preferably at about the reflux temperature of the solvent, and the reaction proceeds advantageously.
  • the 2—pyrrolidinone conjugate represented by the general formula (3) in which the substituent of R ′ has a hydroxyl group is generally used.
  • Examples include trimethyltinsilyl, t-butylinylmethylsilyl, benzyl groups, and the like.
  • These protecting groups may be formed by any known means, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, p-toluenesulfonic acid, acetic acid, oxalic acid, and maleic acid. It can be easily desorbed by organic acids such as laenic acid, or by contacting source.
  • the reaction between compound (3) and compound (7) is generally This is performed in a normal solvent.
  • the solvent is not particularly limited as long as it is not involved in the reaction, and generally, ethyl ether tertiary oxane, tetrahide mouth flank is used.
  • Ethers, halogenated hydrocarbons such as chlorinated / ethylene, chlorinated film, dichloroethane, tetrachloride, benzene, and Aromatic hydrocarbons such as luene and xylene, dimethylformamide, dimethylsulfoxide, hexamethylene triphosphate
  • Non-protonic polar solvents such as mid are used.
  • a suitable condensation aid for example, sodium hydride, lithium hydride, lithium hydride, potassium hydroxide, etc.
  • Basic compounds such as xide, trialkylamine, pyridin, etc., and ruthenium such as anhydrous aluminum chloride, anhydrous second chloride, titanium tetrachloride, etc.
  • An acid is used.
  • the proportions of the compound (3), the compound (7) and the condensation aid may be appropriately selected, but generally the compound (7) and the condensation aid are used in combination with the compound (3). It is advantageous to use a triple molar amount, preferably an equimolar amount.
  • the reaction temperature may be appropriately selected, but in general, the reaction proceeds effectively when the temperature is from 120 to about the reflux temperature of the solvent.
  • 1-strength Lubamoyl-2—pyrrolidinone compound (1) according to the present invention is produced, which is a conventional method for separation, For example, it can be more easily isolated by recrystallization, column chromatography or the like.
  • Lupamoyl 2-Pyrrolidinone compound of the present invention is used to reduce the intellectual weakness of the compound; it also causes neuronal weakness, memory loss, senility or intellectual fatigue, and 'alharhai'.
  • Pharmaceutical forms for administration for the treatment of m-type dementia may be any of oral, injection, suppository, etc., for example. These dosage forms It can be manufactured by young people using the formulation method known to those skilled in the art.
  • the compound of the present invention may contain a shaping agent and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a coloring agent, a odorant, etc. After being added, such additives can be used to produce tablets, granules, powders, capsules, etc. in a conventional manner. Commonly used is good. For example, lactose, white
  • % a sodium nitrate, glucose, starch, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, etc. Then, water, ethanol, and water.
  • disintegrants such as acid sodium, polyvinyl pyrrolidone, and the like include dried starch, sodium alginate, cantan powder, and the like.
  • Hydrogen silicate calcium carbonate, sodium rauryl sulfate, monoglyceride stearate, starch, lactose, etc.
  • lubricants refined talc, stearate, borax, polyethylene glycol, etc. are used as flavoring agents.
  • sucrose, orange peel, citric acid, tartaric acid and the like can be exemplified.
  • One example is rubber and gelatin.
  • pH-controlling agent a so-called pH-controlling agent, buffer, stabilizer, isotonic agent, local anesthetic, etc.
  • examples of the pH adjuster and the adjuvant include sodium citrate, sodium sulphate, sodium sulphate and the like.
  • examples of the stabilizer include sodium bisulfite, EDTA, thioglycolic acid, and thiolactic acid. Is a local anesthetic hydrochloric acid-flops 0 Russia chi-down, hydrochloric acid Li de chi-down Hitoshiryoku f ani-up et al is Ru.
  • the compound of the present invention may be added to a pharmaceutical carrier known in the art, for example, polyethylene glycol, la / lin, cocoa butterfat. , Fatty acid triglycerides, etc., and if necessary, a surfactant such as Tween (registered trademark) is added, and then produced by an ordinary method. You can do it.
  • a pharmaceutical carrier known in the art, for example, polyethylene glycol, la / lin, cocoa butterfat. , Fatty acid triglycerides, etc., and if necessary, a surfactant such as Tween (registered trademark) is added, and then produced by an ordinary method. You can do it.
  • the amount of the compound of the present invention to be incorporated in each unit dosage form described in i, the amount of the compound to be applied depends on the symptoms of the patient or the dosage form, etc. Although it is not constant, it is generally about 1
  • the daily dose of a drug having the above-mentioned dosage form cannot be determined unconditionally depending on the patient's symptoms, weight, age, sex, etc.
  • the present invention is represented by the general formula U). More specifically, according to the synthesis example of Lou 2 —pyrrolidinone conjugate, and the anti-amnesic, anti-anoxic, and acute toxicity tests of compound (2). explain .
  • Example 6 Compound 4 was produced in the same manner as in Example 8
  • a granule of 1000 BIS was prepared per one package according to a conventional method.
  • a tablet of 270 ms per tablet was prepared by the usual method at the above mixing ratio.
  • a capsule preparation of 310 ms per capsule was prepared by the usual method in the above-mentioned compounding house.
  • a suppository of lOOtns was prepared per unit by the usual method at the above mixing ratio.
  • Test example 1 in which an injection was prepared by the usual method at the above mixing ratio
  • Rats Males with a Wistar weight of 70 to 240 g were used in the experiment in groups ranging from 6 to 16 rats.
  • Scopolamine is dissolved in physiological saline and the test compound is dissolved or suspended in 0.5% carboxymethyl cell mouth-snatrium solution.
  • Scopolamine was administered subcutaneously at 0.5 K1 s / ks 30 minutes before the harvest trial, and the test compound was administered orally immediately after the trial.
  • P li ar in aco 1 o 8) 3 Refer to P._, 300-302 (1985), and use a step-thr 0 u sli passive passive learning device.
  • the device is illuminated with 50 s (25] 2 x 30 cm) with a grid floor and 20 lit daylight from above. It consists of a bright room (25 X 12 X 12ctn), and the two rooms are separated by a door. Rats performed a habituation trial approximately one hour before the acquisition trial. In the acclimatization trial, the rat was put into a bright compartment, the door was opened after 5 seconds, and the limb of the rat was completely dark.
  • the retention test is performed 24 hours after the acquisition attempt, and the latency until the rat in the bright compartment moves to the dark compartment. That is, the time during which the passive avoidance reaction was indicated was measured up to 300 seconds.
  • Anti-anoxic effect test effect test on survival time under normal pressure hypoxic load
  • mice were used (dd 5 weeks old, male) with 10 mice per group, referring to the known experimental method.
  • oN is the mouth you have a such transparency blanking la scan switch click container (13 X 13 X 16 c m ), 96% of nitrogen
  • a gas mixture of oxygen and 4% oxygen was passed at a flow rate of 5 minutes. Observation was performed from the start of ventilation to the time when breathing was stopped, and the survival time (seconds) was measured. The results are shown in Table 3 as the percentage increase in survival time compared to control animals.
  • mice Mouse (ddY, 5 weeks old, male) was used as 4 to 5 mice per group.
  • the test compound was dissolved or suspended in 0.5% strength sodium hydroxide solution orally and administered orally, and observed 3 days after oral administration. Deaths were measured. Many of the test compounds show sedation and muscle relaxation symptoms in 30 minutes to 6 hours, then gradually recover, and return to their original condition 2 days later It was. The results are shown in Table 3.
  • the conditions of drugs for the treatment of senile dementia include memory ⁇ cerebral function improving action to improve dysfunction and metabolic activity or injury of brain nerve cells ⁇ It is necessary to have effects such as brain protection that protects from invasion, and furthermore, since the home patient is an elderly elderly person, it has safety with few side effects. ⁇ ⁇ Drugs are desired. Therefore, it can be said that a drug meeting this condition has utility for the treatment of senile dementia.
  • this compound has an anti-amnesic effect and an anti-anoxic effect, and has a cerebral ⁇ activity improving effect and a brain metabolic activity. It has been clarified that it has one effect.
  • LD 5 of this compound in acute toxicity tests The 5 0 0 0 ms / Oh Ru this and force f min in ks above is, was also Ri by ⁇ two La Seta-time shows low toxicity.
  • this compound As described above, the usefulness of this compound is evident because it has both a cerebral function improving effect and a cerebral metabolism activation / protection effect, and has only low toxicity. Yes, it is effective for the treatment of senile dementia.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

Les composés de carbamoyle-2-pyrrolidinone décrits, qui sont utiles comme agents thérapeutiques contre les troubles de la démence sénile, pour améliorer les fonctions cérébrales ou pour activer et protéger le métabolisme du cerveau, sont représentés par la formule (2), où R1 représente un atome d'hydrogène, un groupe hydroxy ou un groupe alkyle inférieur éventuellement à substitution hydroxy, R3 représente un groupe phényle, tétrahydronaphthyle, pyridyle ou thiazolyle éventuellement substitué par un groupe alkoxy inférieur, un groupe alkylamino inférieur, un atome d'halogène ou un groupe halogénométhyle. Sont également décrits de nouveaux composés de carbamoyle-2-pyrrolidinone représentés par la formule générale (1), où R1 représente un atome d'hydrogène, un groupe hydroxy ou un groupe alkyle inférieur éventuellement à substitution hydroxy et R2 représente un groupe phényle, tétrahydronaphthyle, pyridyle ou thiazolyle comportant éventuellement un groupe méthoxy ou un groupe alkyle amino inférieur comme substituant, à condition que R2 ne représente pas un groupe phényle non substitué lorsque R1 représente un atome d'hydrogène ou un groupe alkyle inférieur non substitué.
PCT/JP1989/000401 1988-04-15 1989-04-12 Composes de carbamoyle-2-pyrrolidinone Ceased WO1989009767A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
KR1019890702310A KR910009934B1 (ko) 1988-04-15 1989-04-12 카르바모일-2-피롤리디논 화합물
EP89904600A EP0373226B1 (fr) 1988-04-15 1989-04-12 Composés de carbamoyle-2-pyrrolidinone
DE68916198T DE68916198T2 (de) 1988-04-15 1989-04-12 Carbamoyl-2-Pyrrolidinonverbindungen.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP63/93968 1988-04-15
JP63093968A JP2611803B2 (ja) 1988-04-15 1988-04-15 脳機能改善剤及び脳代謝賦活・保護剤
JP63093967A JP2611802B2 (ja) 1988-04-15 1988-04-15 カルバモイル−２−ピロリジノン化合物
JP63/93967 1988-04-15

Publications (1)

Publication Number Publication Date
WO1989009767A1 true WO1989009767A1 (fr) 1989-10-19

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PCT/JP1989/000401 Ceased WO1989009767A1 (fr) 1988-04-15 1989-04-12 Composes de carbamoyle-2-pyrrolidinone

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US (2) US5229402A (fr)
EP (1) EP0373226B1 (fr)
KR (1) KR910009934B1 (fr)
AT (1) ATE107280T1 (fr)
AU (1) AU615544B2 (fr)
DE (1) DE68916198T2 (fr)
WO (1) WO1989009767A1 (fr)

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US8940771B2 (en) 2007-12-20 2015-01-27 Novartis Ag Organic compounds

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KR910009934B1 (ko) * 1988-04-15 1991-12-06 다이호오 야꾸힌 고오교오 가부시끼가이샤 카르바모일-2-피롤리디논 화합물
FR2647785B1 (fr) * 1989-05-31 1991-09-06 Adir Nouveaux derives de la pyrrolidone, leur procede de preparation et les compositions pharmaceutiques les renfermant
JP2803882B2 (ja) * 1990-02-20 1998-09-24 日清製粉株式会社 １―フエノキシカルボニル―２―ピロリジノン誘導体
IT1242043B (it) * 1990-12-21 1994-02-02 Sigma Tau Ind Farmaceuti Derivati della 1,2,3,4,-tetraidronaftilammina ad attivita' nootropica e composizioni farmaceutiche che li contengono.
JP3719612B2 (ja) * 1993-06-14 2005-11-24 塩野義製薬株式会社 ヘテロ環を含有する尿素誘導体
JP5037767B2 (ja) * 2001-09-19 2012-10-03 キヤノン株式会社 振動型アクチュエータの制御装置
US7021858B2 (en) * 2004-02-12 2006-04-04 Temenuzhka Bencheva Beloreshka Double joints pavement system
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US8404684B2 (en) 2003-05-02 2013-03-26 Novartis Ag Inhibitors of phosphatidylinositol 3-kinase
US8940771B2 (en) 2007-12-20 2015-01-27 Novartis Ag Organic compounds
US8293753B2 (en) 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas

Also Published As

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ATE107280T1 (de) 1994-07-15
US5229402A (en) 1993-07-20
KR900700450A (ko) 1990-08-13
AU3421589A (en) 1989-11-03
EP0373226B1 (fr) 1994-06-15
US5447944A (en) 1995-09-05
EP0373226A4 (en) 1990-09-26
DE68916198D1 (de) 1994-07-21
AU615544B2 (en) 1991-10-03
DE68916198T2 (de) 1994-09-22
KR910009934B1 (ko) 1991-12-06
EP0373226A1 (fr) 1990-06-20

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